2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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1 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Nicef Capsules 250mg / Cefradine Capsules 250mg 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Active Ingredient Cefradine Ph Eur 3 PHARMACEUTICAL FORM Capsules. 4 CLINICAL PARTICULARS Per Capsule 250 mg 4.1 Therapeutic indications Cefradine is indicated for the treatment of infections caused by sensitive Grampositive and Gram-negative bacteria. These include upper respiratory tract infections such as sinusitis, pharyngitis, tonsillitis, laryngo-tracheo bronchitis and otitis media, and also lower respiratory tract infections such as bronchitis (acute and chronic), lobar pneumonia and bronchopneumonia. Cefradine is effective in urinary tract infections including cystitis, urethritis and pyelonephritis. It is also active in skin and soft tissue infections such as abscess, cellulitis, furunculosis and impetigo. The sensitivity of the infective agent to cefradine should be verified, however cefradine therapy may be commenced prior to this determination. The following microorganisms are susceptible, in vitro to cefradine Gram-positive Staphylococci (both penicillin sensitive and resistant strains and penicillinase-producing species) - Streptococci - Streptococci pyogenes (beta haemolytic) - Streptococcus pneumoniae Gram-negative - Escherichia coli - Klebsiella spp - Proteus mirabilis - Haemophilus influenzae - Shigella spp - Salmonella spp (including Salmonella typhi) - Neisseria spp Many strains of E.coli and Staphylococcus aureus that produce the enzyme penicillinase and thus are ampicillin-resistant, are susceptible to cefradine which is unaffected by this enzyme.

2 4.2 Posology and method of administration For oral administration. Adults: Urinary tract infections: 500mg four times daily or 1g twice daily. Infections which are severe or chronic may necessitate the administration of higher doses. Where complications arise including prostatitis and epididymitis, continued intensive treatment is required. Respiratory tract infections : 250 to 500mg four times daily or 500mg to 1g twice daily, dependent on the site and severity of the infection. Skin and soft tissue infections: 250 to 500mg four times daily or 500mg to 1g twice daily, again dependent on the site and severity of the infection. Children: Total daily dose of 25 to 50mg/kg given in two or four equal divided doses. Otitis media: Total daily dose of 75 to 100mg/kg given in divided doses 6 to 12 hourly. Maximum daily dosage: 4g Elderly: The normal adult dose is appropriate. Patients with impaired renal or hepatic function should be monitored during treatment. Renal Impairment The following doses are recommended (based on 500mg every 6 hours) for patients not on haemodialysis: Creatinine Clearance Dosage > 20ml / min 500mg every 6 hours 5-20ml / min 250mg every 6 hours < 5ml / min 250mg every hours. Recommendations for patients on chronic, intermittent haemodialysis: 250mg at the start of haemodialysis 250mg 6 to 12 hours after the start 250mg 36 to 48 hours after the start 250mg at the start of the next haemodialysis session if more than 30 hours have elapsed since the last dose. Additional Information for all patients

3 Regardless of patient age or weight, higher doses of up to 1g four times daily may be required for infections which are chronic or severe. Treatment should continue for at least 2 to 3 days after symptoms have resolved or bacteria have been eradicated. To reduce the possibility of rheumatic fever or glomerulonephritis resulting from infections with haemolytic streptococci, treatment should be continued for at least 10 days. Throughout treatment of chronic urinary tract infections and for several months thereafter, regular bacteriological and clinical monitoring is required. Doses below those recommended above should not be prescribed. Paediatric dosages should not exceed those specified for adults, regardless of severity of infection. It may be necessary to continue cefradine therapy for several weeks in persistent infections. Patients may be transferred from intramuscular/ intravenous cefradine therapy to oral treatment at the same dosage level. 4.3 Contraindications Cefradine should not be used in patients with known or suspected hypersensitivity to cephalosporins. 4.4 Special warnings and precautions for use Prolonged use of an anti-infective may result in the development of superinfection due to the emergence of resistant organisms. Cefradine should be administered with care to patients hypersensitive to penicillins because of the risk of cross-sensitivity between beta-lactam antibiotics. Cephalosporin antibiotics may cause a positive result in Coombs testing. When Coombs testing is performed on neonates whose mothers received cephalosporins prior to labour, it should be noted that a positive result may be due to the drug. Cefradine may cause a false positive urine glucose result when Benedict s or Fehling s solutions or tablets such as Clinitest are used in the testing. This does not occur with enzyme based tests (e.g. Clinistix, Diastix ). Dosage adjustment is necessary in renal impairment (see above). This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4 4.5 Interaction with other medicinal products and other forms of interaction Loop diuretics may increase nephrotoxicity of cephalosporins. Probenecid has been seen to raise serum concentrations of cefradine, by reducing renal clearance of the cephalosporins. There is evidence of partial cross-allergenicity between the penicillins and the cephalosporins. Therefore, cefradine should be used with caution in those patients with known hypersensitivity to penicillin. 4.6 Pregnancy and lactation Although animal studies have not demonstrated any teratogenicity, safety in pregnancy has not been established. Cefradine is excreted in breast milk and should be used with caution in lactating mothers. 4.7 Effects on ability to drive and use machines Since the medicine may cause dizziness, patients should be cautioned about operating hazardous machinery, including automobiles. 4.8 Undesirable effects Limited essentially to gastro-intestinal disturbances and on occasions to hypersensitivity phenomena. The latter are more likely to occur in individuals, who have previously demonstrated hypersensitivity and those with a history of allergy, asthma, hay fever or urticaria. Skin reactions have occasionally been reported. Rare adverse reports include glossitis, heartburn, dizziness, tightness in the chest, nausea, vomiting, diarrhoea, abdominal pain, vaginitis, candidal overgrowth. Skin and hypersensitivity reactions include urticaria, skin rashes, joint pains, oedema. As with other cephalosporins, mild transient eosinophilia, leucopenia and neutropenia, positive direct Coomb s tests and pseudomembraneous colitis have been reported: rare reports of erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis. Blood and lymphatic system disorders Frequency unknown: blood disorders (including thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia and haemolytic anaemia) Immune system disorders Frequency unknown: Fever, serum sickness like reactions, anaphylaxis Psychiatric disorders Frequency unknown: Confusion, sleep disturbances

5 Nervous system disorders Frequency unknown: hyperactivity, hypertonia, dizziness, nervousness Rarely: Headache Hepatobiliary disorders Frequency unknown: Liver, enzyme disturbances, transient hepatitis, cholestatic jaundice Renal and urinary disorders Frequency unknown: Reversible interstitial nephritis Investigations Frequency unknown: Elevation of blood urea nitrogen, serum creatinine, alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase 4.9 Overdose The symptoms of cefradine overdose are non-specific and are generally nausea, vomiting, diarrhoea and gastric upsets. Treatment is mainly supportive although gastric lavage will be necessary if a large amount has been ingested. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Cefradine is a broad-spectrum first generation cephalosporin. It is bactericidal against a wide range of Gram-positive and Gram-negative microorganisms. The reported mode of action is predominantly by the inhibition of cell wall synthesis in susceptible bacteria. This is mainly achieved by inhibiting the trans-peptidation reaction, the final stage of the cell wall synthesis process, thus preventing the complete formation of peptido-glycan cross links. Other earlier stages in this synthesis process may also be inhibited and there may be some induction of bacterial lysis. The stability of cefradine to beta-lactamase enzymes is high. 5.2 Pharmacokinetic properties Cefradine is rapidly and almost completely absorbed from the gastro-intestinal tract. Absorption is delayed although not decreased by the presence of food. Peak plasma levels of 9, 17, and 24 microgram/ml have been achieved 1 hour after respective oral doses of 250mg, 500mg and 1g. The reported plasma halflife is approximately 1 hour; this is increased in renal failure. Plasma protein binding of cefradine is in the range of 6 to 20%. Cefradine is widely distributed in the body entering the bile and crossing the placenta. Cefradine is excreted unchanged by the kidneys with up to 90% of an oral dose appearing in the urine within 6 hours. Oral doses of 250mg, 500mg and 1g produce peak

6 urine concentrations of about 1.6 mg/ml, 3.2mg/ml and 4mg/ml respectively. 5.3 Preclinical safety data No further information additional to that already contained in this SPC. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium Lauryl Sulphate Povidone Colloidal Silicon Dioxide Magnesium Stearate Lactose Monohydrate Capsule Shell Components Sunset Yellow (E110) FD & C Blue 2 (E132) Titanium Dioxide (E171) Gelatin Overprint Ink Constituients Shellac Propylene glycol Black iron oxide (E172) 6.2 Incompatibilities None known. 6.3 Shelf life 36 months. 6.4 Special precautions for storage Store below 25 C (at room temperature). 6.5 Nature and contents of container PVC blisters (250 micron) backed by hard temper aluminium foil (20micron) containing 2, 4, 10, 14, 20, 28, 30, 50, 56, 60, 84, 100, 500 or 1000 capsules. The capsules are size 2 hard gelatin shells with orange body and blue cap overprinted CEPHR250 in black. 6.6 Special precautions for disposal Not Applicable.

7 7 MARKETING AUTHORISATION HOLDER Co-Pharma Limited, Unit 4, Metro Centre, Tolpits Lane Watford Herts WD18 9SS 8 MARKETING AUTHORISATION NUMBER(S) PL 13606/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 28 September DATE OF REVISION OF THE TEXT